OnApril 13, 2013, a meta-analysis performed by theMayo Cliniclooked at3,600 patients and found huge cardiac benefits in those who supplemented withL-carnitine. This study represented the largest, most powerful scientific review of carnitine's cardiovascular benefits to date.

The Mayo Clinic study found carnitine supplementation was associated with a 27% reduction in all-cause mortality, a 65% reduction in ventricular arrhythmias, and a 40% reduction in angina symptoms in patients who had experienced a heart attack. The media largely overlooked this favorable report.

Instead, headline news stories were created based on a report released a week earlier that had asserted that carnitine found in red meat would react with certain gut bacteria in certain individuals to promote a compound (TMAO) that would then cause heart disease.

These findings were based on an evaluation of 10 people. They were obscure, theoretical and preliminary. Yet the media ignored hundreds of studies showing significant cardiovascular benefits to carnitine, choosing instead to use this study in isolation to bash anything that contained carnitine. See below for complete details.

A
recent investigational study published by Koeth et al. in the journal
Nature Medicine1 examined levels of a
compound called trimethylamine-N-oxide
(TMAO) in relationship to microbial metabolism of carnitine in the
gut. The researchers cite very recent, limited
research suggesting TMAO may be a risk factor for cardiovascular
disease. They then provocatively propose that carnitine consumption
may increase cardiovascular risk in some individuals due to
increasing TMAO levels following microbial metabolism of the
compound.

The
authors report the intestinal bacterial flora of people who consume
red meat, a source of dietary carnitine, was conducive to TMAO
production in the presence of carnitine, whereas vegetarians
produced little to no TMAO under the same circumstances.

They
concluded that alterations in the intestinal microbiota associated
with meat consumption may promote the formation of TMAO from
dietary carnitine, and therefore suggested that the carnitine content
of red meat may be one of the reasons it is linked to heart disease.

Following
publication of this study, mainstream media outlets propagated
misleading headlines blaming carnitine for heart disease without
explaining that these findings were very preliminary and that red
meat consumption was required for the observed effect. Life
Extension® members are well aware of the potential health
threats associated with red meat consumption, such as exposure to
saturated fats and advanced glycation end
products,4 and many already consume a
heart-healthy, plant-based diet such as the
Mediterranean diet.

These
deceptive media headlines have generated concern that supplemental
forms of L-carnitine may be detrimental to heart health. This
notion flies in the face of numerous published, peer-reviewed studies
showing L-carnitine promotes cardiovascular health in a variety
of ways. The media's effort to generate headlines has undermined
decades of scientific research on the heart-health benefits of
carnitine.

Ironically,
days after publication of the Koethe et al. carnitine article, a new
meta-analysis of the research on carnitine and heart health
was published by researchers from Mayo Clinic. This large
systematic review provides strong evidence for carnitine's benefits
in heart health. This article examined 13 controlled trials that
enrolled, collectively, 3629 participants, representing the largest,
most powerful scientific review of carnitine's cardiovascular
benefits to date.2

The
authors of the Mayo Clinic study found carnitine supplementation was
associated with a 27% reduction in all-cause mortality,
a 65% reduction in ventricular arrhythmias, and
a 40% reduction in angina symptoms in patients who had experienced
a heart attack. These effects were thought to occur through
multiple mechanisms, including improved energy metabolism
in the mitochondria, decreased ischemia, and enhanced left ventricle
function.2

The
authors describe carnitine as an inexpensive therapy with an
"excellent safety profile" which could
potentially be used in patients
with angina or who are at risk for angina after suffering from a
heart attack. Based on the results of this meta-analysis, the authors
suggest L-carnitine as a potential future therapy for heart attack
and secondary coronary prevention and treatment, including
angina. The scientists state: "Further study with large
randomized controlled trials of this inexpensive and safe therapy
in the modern era is warranted." Unfortunately they also
note: "However, a large trial may never be performed because
L-carnitine is an over-the-counter supplement available to the
public, which decreases the potential revenue compared
with a synthesized [pharmaceutical] product."2

Carnitine's
benefits are well-established and Life Extension® has written about
them at length over the years. The next several paragraphs
describe some of the key health benefits associated with carnitine.

CARNITINE
REDUCES DEATH RATES

The
heart muscle uses fat as its primary energy source. Carnitine is a
fat-transporting compound that is absolutely essential for normal
heart function.5 Over time, the decline of
carnitine plays a role in the weakening of the heart's muscles.6 People
with heart muscle damage due to heart attacks or heart failure have
especially low carnitine levels.7-9 Fortunately,
carnitine supplementation
has proven to be remarkably effective in fighting and even reversing
the heart-weakening effects of that drop in carnitine
levels.6

In
one study, 160 male and female heart attack survivors between 39 and
86 years old received either 4 grams/day of L-carnitine or a
placebo for 12 months.10 The patients taking
L-carnitine experienced significantly favorable decreases in heart
rate and blood pressure;
they also had improved blood lipid profiles. Most importantly, those
supplementing with carnitine had a dramatically reduced
death rate compared to those not taking carnitine. Patients
taking carnitine had a death rate of just 1.2% in the entire year,
while 12.5% of control patients died, with the majority of deaths
attributed to repeat heart attacks.10 L-carnitine
supplementation also prevents the progression of heart muscle damage
in people with congestive heart failure and improves
exercise tolerance in people who develop chest pain (angina) with
exertion.7 In one study, 55% of patients
experienced improvement
in their standard heart failure classification.7

People
with angina, an early sign of impaired blood flow (ischemia) to the
heart muscle, benefited from carnitine supplements. A natural
carnitine derivative (propionyl-L-carnitine), at a dose of 500 mg, 3
times daily, increased the average time patients could exercise
without EKG signs of ischemia by an impressive 450%.17
That result indicated improved blood flow to heart muscle cells
following ischemia, an effect amply demonstrated in animal
studies.11,12

Carnitine
also increases concentrations of nitric oxide, which helps
endothelial cells relax and increase blood flow, an effect that can
help lower blood pressure.13-15 Three weeks of
supplementation with 2 grams of L-carnitine improved blood
flow by 17% during the
critical after-meal period in a group of people fed a high-fat meal;
placebo patients had a 12% decrease in blood flow.16 And
a daily
6-gram intravenous dose of propionyl-L-carnitine for one week
improved walking distance in people with peripheral arterial disease
by 28%.17

CARNITINE
FIGHTS DIABESITY

As
obesity rates skyrocket, more and more Americans are
developing type II diabetes as a result, producing a syndrome
called "diabesity."18,19

Since
carnitine helps the mitochondria utilize energy, it plays a critical
role in reducing the occurrence and impact of diabesity.20 Recent
studies show that in addition to helping the mitochondria burn fat as
energy, carnitine is also vital for removing waste products
from mitochondria.21,22 This is important because
we now recognize that the buildup of mitochondrial waste products is one
of the most important contributors to insulin resistance, which
further promotes high blood sugar and obesity.23

Obesity
and aging contribute to low carnitine levels, which compromises
mitochondrial performance and increases insulin resistance,
promoting further obesity and carnitine reduction. Restoring
carnitine levels to their youthful values is an effective way to break
this deadly cycle.21 Human
volunteers who took L-carnitine 3 grams/day for 10 days had
favorable changes in body composition.24 Supplemented patients
used their fat for energy, burning it 22% faster than control
patients, without any increase in muscle protein breakdown.
In another study, using 2 grams/day for 6 months, demonstrated
a loss of total fat mass of 4 pounds, with a gain in
lean muscle mass of 8.4 pounds.25

Animal
studies confirm and extend these findings, showing that
propionyl-L-carnitine decreases body weight gain, food intake, and fat
composition while improving insulin resistance.20 Carnitine
also has multiple favorable effects on elevated blood sugar and
insulin resistance, the hallmarks of type II diabetes.22 Animals
fed a high fat diet develop the same symptoms and signs that humans
do: obesity, insulin resistance, abnormal lipid profiles,
and liver damage, which are known as metabolic syndrome.
Just 4 weeks of treatment with L-carnitine reversed all of those
abnormal parameters.18,26-28 Similar
effects have been found in diabetic humans. Two grams of
L-carnitine twice daily for 10 days improved insulin sensitivity
and reduced insulin levels.29 L-carnitine
supplementation of two grams/day caused a significant
reduction in plasma free
fatty acids, which contribute to insulin resistance.30
Three grams/day were shown to reduce simulated
after-meal blood sugar
spikes from 157 mg/dL to 132 mg/dL (oral glucose tolerance test).31
A significant number of studies document the deadly impact
of elevated after-meal glucose levels.

CARNITINE
PROTECTS AGAINST HEART DISEASE

Research
suggests that a specific form of carnitine, called
propionyl-L-carnitine (PLC), plays an important role in protecting
the function
and health of endothelial cells.32-34 Studies
also indicate that PLC may act as a nutritional corrective agent,
relieving clinical
symptoms of cardiovascular conditions such as peripheral arterial
disease, angina, coronary artery disease, cardiomyopathy,
intermittent claudication, ischemic heart disease, atherosclerosis,
and congestive heart failure.35-42 PLC appears to
be more potent than L-carnitine in improving vascular function.43 PLC
passes across the mitochondrial membrane to supply L-carnitine
directly to the mitochondria, the energy-producing organelles of
all cells. This is important because heart muscle cells and
endothelial cells burn fatty acids rather than glucose for 70% of
their energy.
By contrast, most cells generate 70% of their energy from glucose and
only 30% from fatty acids.44

Carnitine
deficiency has been associated with congestive heart failure.51
PLC supplementation has been reported to increase exercise
capacity, optimize energy production, and reduce ventricular size in
patients with congestive heart failure.38 The
myocardium, the muscular substance of the heart, comprises cells
called cardiomyocytes. A study of cardiomyocytes found that
PLC helped to correct an imbalance between the production and
utilization of adenosine triphosphate (ATP), the energy currency
used throughout the body. This suggests that PLC may improve cardiac
performance by improving energy metabolism and optimizing
ATP levels.45 An
animal study suggests PLC may help to prevent or decrease the
severity of atherosclerosis. In rabbits fed a high-cholesterol diet,
which normally induces endothelial dysfunction and subsequent
atherosclerosis, supplementation with PLC resulted in reduced
plaque thickness, markedly lower triglyceride levels, and reduced
proliferation of foam cells, thereby preventing the progression
of atherosclerosis.41

PLC
has been shown to have a protective role against vascular cell
inflammation that other carnitines do not. When rodents were exposed
to irritating chemicals, PLC protected their vascular cells from this
source of damage, but L-carnitine and acetyl-L-carnitine did
not, leading the study authors to support "a specific protective
role of PLC in the vascular component of the inflammatory process."33 PLC
improves endothelial function by increasing nitric oxide production
in animals with normal blood pressure and in animal models of
hypertension. The increased nitric oxide production induced by PLC is
related to its antioxidant properties; PLC reduces reactive oxygen
species and increases nitric oxide production in the endothelium in
the presence of superoxide dismutase (SOD) and catalase.46 Oxygen-deprived
endothelial cells produce large amounts of free radicals. Laboratory
findings suggest that PLC protects these cells during
periods of oxygen deprivation. When blood flow is restored, PLC also
allows the cells to regain their lost energy charge much faster.34 An
animal study indicates that PLC prevents abnormal heart muscle
function associated with diabetes. The researchers found that PLC
significantly increased both fatty acid and glucose utilization while
restoring cardiac muscle function. These findings suggest PLC
prevents diminished cardiac function associated with diabetes,
possibly by promoting a favorable shift in glucose and fatty acid metabolism.47

The
totality of these numerous studies contradicts the report that
carnitine in red meat diets increases atherosclerosis risk.

LIFE
EXTENSION CONDUCTS SURVEY OF MEMBERS USING CARNITINE SUPPLEMENTATION

As
part of a thorough evaluation of this issue, Life Extension's Health
Advisors spoke to a representative sample of 115 customers who
supplement with carnitine and inquired as to their experience with
the compound. Not surprisingly, not one member reported having
a cardiovascular event such as a heart attack or stroke after
initiation of carnitine supplementation. On the contrary, many
customers reported their cardiovascular health improved after
they started supplementing with carnitine. Although there are limitations
to anecdotal reports, actual Life Extension customers using carnitine
for health purposes nevertheless reported a variety of
benefits (full names not disclosed for confidentiality purposes):

n
H.W. reported having chest pain (angina), shortness of
breath, and being diagnosed with atrial fibrillation a few years ago. Within
days after starting carnitine supplementation his endurance increased
significantly and he no longer experienced shortness
of breath. He is now able to exercise regularly.

n
M.M. stated that his physician noted his blood pressure
was very good for his age; he attributed his excellent cardiovascular health
to carnitine supplementation.

n
L.C., who has a history of heart palpitations, reported
that supplemental carnitine helps alleviate her heart fluttering.

n
R.L. reported he used to need to oxygen therapy from
time to time, but since he started supplementing with carnitine he no longer
requires it.

n
F.B., who had high blood pressure in the past, reported
that his blood pressure has been under control since he started supplementing
with carnitine.

n
V.P. has a congenital heart defect and reported that
function of her heart valves improved after she started taking
carnitine. She
reported also that carnitine helped reduce her heart enlargement,
which was a consequence of her congenital heart defect.

n
P.V., who has a history of atrial fibrillation,
reported that since using carnitine he has not experienced any atrial
fibrillation.

SUMMARY
EXAMINATION OF THE MEDIA-HYPED CARNITINE ARTICLE EXPOSES SEVERAL
PROBLEMS

Despite
the media attention given to the study published in Nature
Medicine by Koeth et al., caution must be used when applying the
results to cardiovascular risk. Life Extension® has carefully
examined this study and identified the following factors with this study
that are summarized below.

1.
Limited research on TMAO and associated effects on human health
prevents causal interpretation at this time. A search
of the peer-reviewed literature using terms "TMAO" and
"atherosclerosis" yields only 3 results, with the
first suggestion
of a potential association in 2011.48 Correlation
is not causation, and in fact, TMAO is found in relatively large quantities
in fish, a food that is linked to a markedly reduced risk of
cardiovascular events. In contrast, components of red meat
such as saturated fat raise LDL cholesterol, and a search of the
peer-reviewed literature using the terms "LDL," "cholesterol,"
and "atherosclerosis" returns over 10,500 results.

2.
Only 10 human subjects were examined in carnitine supplementation
substudy. The researchers used only 10 subjects
in their small substudy of carnitine supplementation and TMAO levels.
This is a very small data set with which to make
such sweeping conclusions. Since so few humans were directly examined
in this context, the validity and applicability
of the scientists' findings are questionable at best.

The
study by Koeth et al. focused upon the metabolic conversion of
L-carnitine to TMAO by gut bacteria, and the differences in
the gut microbiome between red meat eaters and vegetarians. In fact,
many studies show that L-carnitine has a variety of beneficial
effects upon cardiovascular function, including prevention of the
progression of atherosclerotic lesions. For example,
one study reported that in the context of hypercholesterolemia,
L-carnitine supplementation "completely prevented the
progression of atherosclerotic lesions induced by
hypercholesterolaemia in both aorta and coronaries."49
In another study,
supplementation with propionyl-L-carnitine (PLC), a derivative of
carnitine used as a drug in Europe for treatment of atherosclerosis,
"induced a marked lowering of plasma triglycerides, very low
density lipoprotein (VLDL) and intermediate density
lipoprotein (IDL) triglycerides…" while plasma cholesterol
was slightly and transiently reduced. In addition, PLC treatment
"…exhibited a reduction of plaque thickness and extent…and
a reduction of the number of both proliferating macrophage-
and smooth muscle cell-derived foam cells."41
Foam cells are precursors to atherosclerotic lesions.

4.
Published, peer-reviewed evidence shows L-carnitine effectively
treats peripheral artery disease caused by atherosclerosis.
Intermittent claudication (IC) is a painful, atherosclerotic syndrome
that is known to be caused by peripheral
artery disease.50 A 2013 systematic review of 40
articles on IC found that L-carnitine demonstrates a benefit in functional
performance with carnitine supplementation. The authors suggest
routine supplementation with carnitine "may therefore
be a useful adjunct therapy for management of intermittent
claudication."51

5.
Heavy red meat consumption is a known, well-validated risk factor
for atherosclerosis in contrast to plant-based diets.
In the study by Koeth et al., L-carnitine alone did not raise TMAO
levels — the increases in TMAO were observed when
L-carnitine was exposed to the bacterial gut microbiome of red meat
eaters in comparison with vegetarians' gut microbiome.
Extrapolation of these preliminary test results involving the gut
microbiome in heavy red meat eaters is not representative
of health conscious individuals who typically limit red meat
consumption given the known adverse health effects
associated with a diet rich in red meat.

6.
Heart-healthy salmon is associated with high TMAO levels.
Consistency of association is critical in order to draw conclusions
from study data across the published literature. The fact that
heart-healthy fish consumption is associated with an
increase in TMAO levels is challenging to reconcile with the idea
that TMAO necessarily causes atherosclerosis. For example,
Lloyd et al.52 reported that consumption of
salmon, a food known for cardiovascular health benefits, led to an increase
in TMAO levels in human test subjects. In another study, it was also
observed that TMAO levels increased in individuals
consuming large amounts of seafood products.53

8.
The gut microbiome of red meat eaters is different from
vegetarians. In this study vegans had almost no increase in TMAO
levels. It was suggested that this was due to a different gut
microbiota that develops in vegetarians compared to omnivores.
Health conscious people have long known of the potential adverse
effects of diets rich in red meat given the multiple
cardiovascular risks associated with ingestion of red meat.

9.
Probiotic supplementation may modulate gut microbiota and suppress
formation of TMAO. Not all gut bacteria strongly
generate TMAO. On the contrary, certain strains of commensal bacteria
have been shown to manipulate the gut microbiome
in a manner favorable to human health. Specifically, members of the
Lactobacilli species were inversely associated
with TMAO in the human subjects examined by Koeth et al. Also,
Lactobacilli spp. have been shown to increase the
ratio of genus Bacteroidetes to genus Firmicutes in the
human intestine following oral administration; this is important because
many species of the Firmicutes genus were shown to produce
TMAO by Koeth et al. (though the associations were not
consistent across all species of Firmicutes tested).54
In addition, Koeth et al. showed that antibiotics, by
suppressing intestinal
bacterial colonization, virtually abolished TMAO formation. While
antibiotic prophylaxis is not an ideal method for reducing
TMAO formation since it also eliminates beneficial intestinal
bacteria, evidence suggests that certain members of the
probiotic species Bifidobacterium and Lactobacilli may
generate antibiotic-like metabolic byproducts called short-chain fatty
acids that modify the intestinal microbiota in a favorable way.55

50.
Available at:
http://www.mayoclinic.com/health/claudication/DS01052/DSECTION=symptoms.
Last update January 2012.

Accessed
April 8, 2013.

51.
Atherosclerosis. Mar 15 2013.

52.
Am J Clin Nutr. Oct 2011;94(4):981-991.

53.
Nature. May 15 2008;453(7193):396-400.

54.
Clin Nutr. Mar 4 2013.

55.
PLoS One. 2012;7(10):e47212.

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